Genetic epidemiologic studies have demonstrated that schizophrenia is substantially heritable, but the disorder's molecular genetic basis remains elusive. In view of evidence that genes predisposing to schizophrenia may be transmitted without expression of the clinical phenotype, our strategy has focused on elucidating neurobiological and neuropsychological correlates of genetic predisposition that could be used as phenotypic indicators in linkage studies. In the initial funding period of this ROl we utilized a discordant twin pair design to examine neuroanatomical and neuropsychological measures as endophenotypic indicators of schizophrenia. We recruited and evaluated a representative sample of 60 twin pairs discordant for schizophrenia (30 monozygotic [MZ], 30 dizygotic [DZ]) and 60 demographically-similar control pairs (30 MZ, 30 DZ) with DNA-based tests of zygosity, structured diagnostic interviews, neuropsychological testing, and magnetic resonance imaging (MRI) scans of the brain. Impaired performance on tests of spatial working memory and structural abnormalities in the frontal region on MRI were found to vary in a dose-dependent fashion with degree of genetic loading for schizophrenia (i.e., the deficits were greater in the MZ compared with DZ co-twins of schizophrenics). No other cognitive function assessed in our comprehensive battery and no other structural indicator from the MRI assessment showed as strong or consistent a relationship with level of genetic predisposition to schizophrenia. Prior animal and human work indicates that the dorsolateral prefrontal cortex (DLPFC) mediates working memory functions as part of a distributed neural system involving dopaminergic and glutamatergic mechanisms. We now propose to examine the same series of twins with functional MRI and event related potential methods during performance of verbal and spatial working memory tasks in order to test the hypothesis that patients and their co-twins manifest disturbances in a DLPFC-working memory circuit and to examine the extent of this dysfunction according to the various possible points of functional/anatomical fractionation within working memory. We will also evaluate subgroups of the previously-ascertained twins with positron emission tomographic (PET) methods to determine whether patients and their co-twins evidence a reduction in dopamine D1 receptors in the DLPFC, whether co-twins evidence increased subcortical dopamine release alter infusion of the glutamatergic receptor antagonist ketamine, and whether these molecular changes are correlated with DLPFC activity during working memory processing.